The molecular dynamics of MDM2.

The pro-oncogenic signals of a vast number of anti-cancer drug targets are mediated by protein-protein interactions. This has made such targets less attractive to classic drug discovery programmes. New paradigms in the protein science field have revealed, however, that many protein-protein complexes are stabilized by an interaction between an intrinsically disordered peptide motif and a highly structured globular domain. This type of protein-protein interaction embodied by the MDM2-p53 complex can form a drugable interface. Extensive research has already uncovered the structure of the MDM2-bound p53 peptide to create p53 mimetics like Nutlin, but there has been less emphasis on understanding the dynamic nature of MDM2 itself. The work summarized by Joseph et al. forms a comprehensive and innovative roadmap using molecular dynamics simulations that provide solutions for understanding the flexible nature of a peptide-protein interface. This includes concepts on the plasticity of the peptide-binding groove and induced-fit mechanisms that explain the diversity of linear peptide motifs accommodated by globular domains. The success of molecular dynamics should inspire us to build further the structural biology of full-length MDM2 and other challenging oncoproteins for developing rules on how to develop small molecules that allosterically regulate multi-protein complexes.